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5-플루오로우라실 프로드럭의 제조, 물리화학적 성질 및 항암효과
지웅길(Ung Kil Jee),이계원(Gye Won Lee) 대한약학회 1996 약학회지 Vol.40 No.3
To assess their stability as a prodrug of 5-fluorouracil (5-FU), four N-acyloxycarbonyl derivatives (1-(N-tert-butyloxycarbonyl)glycyloxymethyl-5-FU :BGFU, 1-(N-tert-butyloxycarbonyl)-leucyloxymethyl-5-FU:BLFU, 1-(N-tert-carbobenzyloxymethyl) glycyloxymethyl-5-FU:CGFU and 1-(N-tert-carbobenzlyoxymethyl)leucyloxymethyl-5-FU:CLFU) possessing differently protected amino acids, and two acetic acid derivatives (5FU-1-acetylpentane:FUAP and 5-FU-1-acetylhexane:FUAH) were synthesized and their physicochemical properties, hydrolysis kinetics, acute toxicity and antitumor activity were evaluated. The lipid-water partition coefficients of six 5-FU prodrugs were higher than that of 5-FU and their aqueous solubilities were in the following rank order; BGFU>FUAP>CGFU>BLFU>CLFU=FUAH. The hydrolysis of N-acyloxycarboyl derivatives, greater at higher pH, was enhanced in presence of liver homogenate or human plasma. Meanwhile, acetic acid ester derivatives, very stable, were hydrolyzed by liver homogenate. Absorption rate constants were 0.181, 0.121, 0.111, 0.168, 0.168, 0.116 and 0.125 hr-1 for 5-FU, BGFU, BLFU, CGFU, CLFU, FUAP and FUAH, respectively. The cytotoxicity of N-acyloxycarbonyl derivatives was 4 to 5 times lower than that of 5-FU, but that of acetic acid ester derivatives was negligeble. The LD50 values were 204, 325.97 (133.59, amount as 5-FU), 708.16 (262.13), 663.50 (211.77), 382.33 (192.54) and 272.33 (130.09) mg/kg for 5-FU, BGFU, CGFU, CLFU, FUAP and FUAH, respectively. While N-acyloxycarbonyl derivatives showed enhanced antitumor activity and therapeutic ratio (3.30, 3.06, 4.19, 3.11 and 1.81 for BGFU, BLFU, CGFU, CLFU and 5-FU, respectively), FUAH and FUAP showed a smaller therapeutic ratio (0.79 and 0.83).
리포좀에 봉입한 5-플루오로우라실 프로드럭의 세포독성, 안정성 및 항암효과
이계원(Gye Won Lee),지웅길(Ung Kil Jee) 대한약학회 1996 약학회지 Vol.40 No.5
5-fluorouracil(5-FU) derivatives synthesized with four N-acyloxycarbonyl group such as 1-(N-t-butyloxycarbonyl)glycyloxymethyl-5-FU(BGFU), 1-(N-t-butyloxycarbonyl)leucyloxymethyl-5-FU(BLFU), 1-(N-t-carbobenzyloxymethyl)glycyoxymethyl-5-FU(CGFU) and 1-(N-t-carbobenzyloxymethyl)leucyloxymethyl-5-FU(CLFU) were entrapped into liposomes with different lipid compositions. The entrapment efficiency and release rate of drugs from each liposomes were evaluated. The particle size of liposomes, cytotoxicity and stability of drug-entrapped in liposomes were evaluated. The entrapment efficiency in 5-FU derivatives liposomes was dependent on the lipophilicity of N-acyloxymethyl derivatives. The drug entrapment efficiency also increased on the content of lipid increased up to 200mcmol of lipid per milliliter of liposomal solution. However, inclusion of additives such as cholesterol, dicetylphosphate and stearylamine decreased the entrapment efficiency. The mean particle size and size distribution were varied with lipid compositions and lipophilicity of prodrugs. The release rates of drugs from liposomes were not affected by additives, but those of BGFU and CGFU entrapped in liposomes with cholesterol decreased. Cytotoxicity of BLFU and CLFU entrapped in liposomes decreased by 3~5 fold compared with those of free two prodrugs. Liposome-entrapped 5-FU prodrugs were more stable either at pH 7.4 or in human plasma. Especially, 5-FU prodrugs entrapped in liposome with dipalmitoylphosphatidylcholine(DMPC) was the most stable in human plasma. Compared with free BLFU, BLFU entrapped in DMPC liposome showed a superior antitumor activity at all doses used. In contrast, CLFU entapped in liposomes were more toxic than free prodrug.
$OMP-{\beta}-CD$ 포접화합물의 물리화학적 성질, 안정성 및 피부 투과 실험
이상영,이계원,최현순,지웅길,Lee, Sang-Young,Lee, Gye-Won,Choi, Hyun-Soon,Jee, Ung-Kil 한국약제학회 1997 Journal of Pharmaceutical Investigation Vol.27 No.4
Because omeprazole(OMP) is very unstable in aqueous condition, $OMP-{\beta}-CD$, the inclusion complex of OMP and ${\beta}-cyclodextrin({\beta}-CD)$ was made and physicochemical properties of it were compared with those of OMP. Skin permeability of OMP and $OMP-{\beta}-CD$ in propylene glycol vehicle and the reciprocal action of ${\beta}-CD$ with various enhancers were examined through hairless mouse. Adhesive patches were prepared with polyisobutylene and the skin permeability and stability of OMP were investigated. The inclusion complex showed higher solubility and lower partition coefficient than OMP itself. DMSO, 1-methyl 2-pyrrolidone and sodium cholate had an enhancing effect. However ethanol and polysorbate 80 hardly showed the enhancing effect of OMP. When sodium lauryl sulfate and sodium cholate as enhancer were added in patch, the former case showed higher permeability of OMP.
리포좀에 봉입된 5-플루오로우라실 프로드럭의 약물 동태 및 장기 분포
이계원(Gye Won Lee),지웅길(Ung Kil Jee) 대한약학회 1996 약학회지 Vol.40 No.5
In cancer chemotherapy, it is necessary to control the phamacokinetic behavior of an antitumor drug for effective treatment. Therefore, two 5-fluorouracil derivatives synthesized with N-a-cyloxycarbonyl derivatives {1-(N-t-butyloxycarbonyl)leucyloxymethyl-5-FU(BLFU) and 1-(N-t-carbobenzyloxymethyl)leucyloxymethyl-5-FU(CLFU)}. prodrugs of 5-fluorouracil, antitumor agent, were loaded into liposome of different lipid compositions. After liposomal drugs were injected intramuscularly, their pharmacokinetics and tissue distribution were assessed. The AUC0->infinity values were 1.29, 72.50, 85.57, 66.40 and 103.60mcg.hr/ml for 5-FU, BLFU, CLFU, BLFU- and CLFU-loaded liposome, respectively. 5-FU was distributed to spleen and liver with a maximal concentration after 1 hr and eliminated after 24 hr. But both prodrugs and dimyristoylphosphatidylcholine liposome entrapped prodrugs were distributed to spleen and liver at a lower concentration but maintained for a long time with a relatively high concentration in lung. Especially, liposome-entrapped CLFU was distributed to lung with a maximal concentration after 1 hr and redistributed to spleen increasingly, while the concentration of liposome-entrapped BLFU in lung reached a maximal level after 12 hr.
2-HP-β-시클로덱스트린과 메글루민을 이용한 란소프라졸의 포접화합물 제조 및 평가
이정우,김정수,장혜진,이계원,지웅길,Lee, Jung-Woo,Kim, Jung-Su,Chang, Hye-Jin,Lee, Gye-Won,Jee, Ung-Kil 한국약제학회 2004 Journal of Pharmaceutical Investigation Vol.34 No.4
To enhance the solubility and stability of lansoprazole (LAN), new proton pump inhibitor, we were prepared various molar ratio of inclusion complex with $2-hydroxypropyl-{\beta}-cyclodextrin$ (HPCD) and organic alkali agent, meglumine (MEG). Inclusion complex formation of LAN with HPCD was investigated by Differential Scanning Calorimetry and X-ray diffractometry. The aqueous solubilities of inclusion complexes, and the stabilities of 1:4 and 1:5 inclusion complexes in aqueous solutions containing different concentrations of MEG were examined. The stability of 1:5 LAN-HPCD inclusion complex containing MEG, which was equaled to amount of LAN, was performed in 0.9% NaCl and 5% dextrose solution. The formation of inclusion complex of LAN with HPCD was $A_L$ type and the molar ratio of complex was 1:1. The stability constant was $41.557\;M^{-1}$. As molar ratio of LAN to HPCD was increased, solubility of inclusion complex was increased. 1:5 LAN-HPCD inclusion complex was more stable than 1:4 LAN-HPCD inclusion complex. And as contained MEG amount in LAN solution was increased, stability of 1:4 and 1:5 LAN-HPCD inclusion complexes was improved. Also stability of 1:5 LAN-HPCD-MEG inclusion complex in 0.9% NaCl solution and 5% dextrose solution was similar to it in water at room temperature, but it was unstable at $40^{\circ}C$.
마이크로에멀젼을 이용한 프로포폴 주사제의 개발 및 평가
이종화(Jong Hwa Lee),박선영(Sun Young Park),김동우(Dong Woo Kim),조미현(Mi Hyun Cho),조인숙(In Suk Cho),이계원(Gye Won Lee),박목순(Mork Soon Park),지웅길(Ung Kil Jee) 대한약학회 2002 약학회지 Vol.46 No.5
Propofol(2,6-diisopropyl phenol) is a phenol derivative that is chemically distinct from other intravenous serdative hypnotics. It has been extensively used as a short term anesthetic agent, because of the rapid onset and short duration of action. Propofol microemulsion system was prepared with different concentrations of ethyl oleate, Solutol(R) HS 15 and Kollidon(R) 17 PF Propofol microemulsions were studied by transmittance, viscosity, Particle size, in vitro release and Pharmacokinetics. The range of transmittance of A group with 4% ethyl oleate and that of B group with 5% ethyl oleate were 2.6-95.1 and 91.3∼94.2%, respective17: Transmittance 1∼2% decreased as concentration of Kollidon(R)17 PF was increased and increased 0.8∼3.3% when 10 times diluted with normal saline. The viscosity of A and B group were in the range of 3.9∼ 4.1 mPa ·sec and 4.4∼5.3 mPa ·sec, respectively: The particle sizes of A and B group increased as amount of Kollidon(R) 17 PF Also, release of propofol was slowly increased as the amount of Kollidon (R) 17 PF was increased. Propofol plasma concentration by 1.v injection showed 2-compartment model. Pharmacokinetics of A-5 was similar to that of commercial emulsion(POFOL).